Biclonal Diffuse Large B-cell Lymphoma Commonly Characterized by Partial Trisomy 18q Involving MALT1 and BCL2.

A 68-year-old man was admitted because of a left shoulder mass and swollen right testis. Pathological examinations indicated a diagnosis of diffuse large B-cell lymphoma (DLBCL) with the CD20+BCL6+MUM1+BCL2+CD10-MYC- phenotype in both lesions. G-banding of soft tissue showed 47,XY,+18, whereas testicular cells showed 47,X,+X,-Y,der (4) t (4;18) (p15;?),del (5) (q?),+13. Fluorescence in situ hybridization detected additional MALT1 and BCL2 signals in both lesions. Southern blot demonstrated different IGH rearrangements between the soft tissue and testis. The patient was diagnosed with biclonal DLBCL with different karyotypes but similar immunophenotypes. Partial trisomy 18q involving MALT1 and BCL2 may be commonly involved in the pathogenesis of this biclonal DLBCL.

[Long-Term Survival of a Patient with Hepatocellular Carcinoma after Surgical Resection of Metachronous Hilar Lymph Node Metastases].

The recurrence of hepatocellular carcinoma(HCC)is primarily due to intrahepatic metastases. Additionally, extrahepatic HCC metastases most commonly occurs in the lungs, lymph nodes, adrenal glands, and bones. Systemic chemotherapy is the standard treatment for extrahepatic metastases. Although several reports on surgical resection of lymph node metastases (LNM) in patients with HCC have been published, its clinical benefits remain controversial. We report a case in which surgical resection of LNM was performed in a patient with HCC. The patient was a 74-year-old woman diagnosed with HCC and non-B non-C chronic hepatitis, for which she underwent a laparoscopic partial hepatectomy. The pathological diagnosis was St-A, 1.6×1.4 cm, confluent multinodular type, pT1N0M0, fStage Ⅰ. Nine months later, 2 LNM on the liver hilum were detected and managed with sorafenib. Sorafenib was discontinued after 2 months due to the development of Grade 3 hand-foot syndrome. Since no new lesions were detected on follow-up, lymph node resection was performed. The patient remains disease-free 4.5 years postoperatively.

MYB Translocations in Both Myoepithelial and Ductoglandular Epithelial Cells in Adenoid Cystic Carcinoma: A Histopathologic and Genetic Reappraisal in Six Primary Cutaneous Cases.

ABSTRACT: Adenoid cystic carcinoma (ACC) is an infiltrating carcinoma composed of 2 cell types, myoepithelial and ductoglandular epithelial cells. Although approximately 70% of ACC exhibit translocations of the MYB proto-oncogene or MYB proto-oncogene like 1 (MYBL1), expression of MYB is known to be limited in myoepithelial cells. We investigated the histopathologic and genetic characteristics of ACC in 6 primary cutaneous cases. Histopathologically, 3 cases (50%) exhibited well-demarcated nodules composed of large nests, easily misdiagnosed as polymorphous sweat gland carcinoma. Two cases (33%) harbored large cystic structures resembling spiradenoma, hidradenoma, and digital papillary adenocarcinoma. A papillary pattern was focally observed in 2 cases (33%). A melting phenomenon within the myxoid stroma was seen in one case (17%). Fluorescence in situ hybridization (FISH) revealed MYB break-apart in 3 cases (50%). A combined FISH and immunohistochemical method revealed MYB break-apart signals in both p63-positive myoepithelial and p63-negative ductoglandular epithelial cells, suggesting that both cell types constitute elements of the tumor in ACC. Moreover, we established a well-circumscribed variant of ACC and proposed 3 new patterns of cystic, papillary, and melting in addition to the 3 patterns of cribriform, tubular, and solid growth.

EWSR1-CREM fusion in pulmonary mesenchymal neoplasm showing distinctive clear cell morphology.

EWSR1-CREM gene fusions were recently discovered in several mesenchymal and epithelial tumors, including myxoid mesenchymal tumors of the central nervous system, rare cases of soft tissue clear cell sarcoma and angiomatoid fibrous histiocytoma, and hyalinizing clear cell carcinoma, which implicates the potential phenotypic diversities of tumors harboring an EWSR1-CREM fusion. We herein present an exceedingly indolent pulmonary mesenchymal tumor showing distinctive clinicopathological features. This tumor histologically displayed a small nest and alveolar pattern consisting of monomorphic clear cells intermingled with dilated anastomosing vasculature. Immunophenotypically, tumor cells were positive for vimentin and focally positive for synaptophysin, but negative for many immunohistochemical panels including keratins, EMA, desmin, mesothelial markers, melanotic markers, smooth muscle actin, inhibin and S-100 protein. Interestingly, RNA sequencing identified an in-frame EWSR1-CREM fusion, which was confirmed by subsequent real-time/reverse transcription polymerase chain reaction and fluorescence in situ hybridization assay. Clinical follow-up showed no evidence of recurrence and metastasis. Our pathological findings further expand the phenotypic spectrum of tumors associated with EWSR1-CREM fusions, implying the emergence of a possible novel tumor entity.

Autoimmune Myelofibrosis in Sjögren's Syndrome: Report of a Case.

BACKGROUND Autoimmune myelofibrosis (AMF) is a rare clinicopathologic entity of bone marrow fibrosis that occurs in association with autoimmune disorders. Steroids are very effective for treatment of AMF and the disease has a good prognosis and should be distinguished from primary myelofibrosis. CASE REPORT A 49-year-old man with bleeding and petechial hemorrhage of the extremities presented to our institution. His platelet count was 1×109/L. Bone marrow aspiration revealed a dry tap, and bone marrow biopsy confirmed small lymphocyte infiltration and increased reticular fibers, consistent with immune thrombocytopenia. Testing for mutations in JAK2, MPL, and CALR was negative. Because the patient had a history of Raynaud's phenomenon, he was suspected to have collagen disease. Anti-Sjögren's-syndrome-related antigen-A antibody testing, Schirmer's test, and fluorescein staining all came back positive, which led to a diagnosis of Sjögren's syndrome. Given the bone marrow findings, the patient also was diagnosed with AMF. Treatment with steroids resulted in an immediate improvement in his platelet count. CONCLUSIONS In the present case, treatment with steroids resulted in prompt improvement in platelet counts and subsequent marrow biopsy showed MF-0 reticulin fibrosis. Bone marrow fibrosis rarely is seen in association with autoimmune disease, and its significance and mechanism are still to be determined.

Soft tissue tumor with novel NR1D1-MAML1 fusion in a pediatric case.

We herein describe soft tissue tumor arising in the lower extremity of a pediatric patient. The tumor displayed a unique and wide range of histological features, sheet-like and cohesive growth pattern consisting of enlarged round to epithelioid atypical cells with a large alveolar and pseudopapillary histological architecture, focally mimicking alveolar soft part sarcoma and MiT family translocation renal cell carcinoma. Tumor cells were focally immunoreactive for cytokeratin, S-100, and EMA. RNA sequencing identified a novel in-frame NR1D1 (exon 5)-MAML1 (exon 2) gene rearrangement resulting in the formation of a putative chimeric protein containing the N-terminal C4-type zing finger domains of NR1D1 and the C-terminal MAML1 protein, which was confirmed by subsequent RT-PCR, Sanger sequencing, and FISH assay. To the best of our knowledge, NR1D1-MAML1 fusion has not yet been described in any neoplasms, suggesting the emergence of a novel tumor entity.

MYC amplification on double minute chromosomes in plasma cell leukemia with double IGH/CCND1 fusion genes.

In multiple myeloma (MM), MYC rearrangements that result in increased MYC expression are associated with an aggressive form of MM and adverse outcome. However, the consequences of MYC amplification in MM remain unclear. Here, we describe an unusual case of plasma cell leukemia (PCL) harboring MYC amplification on double minute chromosomes (dmin). A 79-year-old woman was initially diagnosed as having BJP-κ type MM with bone lesions. After seven months, the disease progressed to secondary PCL: leukocytes 49.1 × 109/L with 77% plasma cells showing lymphoplasmacytic appearance. The bone marrow was infiltrated with 76% plasma cells immunophenotypically positive for CD38 and negative for CD45, CD19, CD20, and CD56. The karyotype by G-banding and spectral karyotyping was 48,XX,der(14)t(11;14)(q13;q32),+der(14)t(14;19)(q32;q13.1),+18,6~95dmin[15]/46,XX[5]. Fluorescence in situ hybridization detected multiple MYC signals on dmin and double IGH/CCND1 fusion signals on der(14)t(11;14) and der(14)t(14;19). Most plasma cells were diffusely and strongly positive for MYC and CCND1 by immunohistochemistry. The patient died of progressive disease after one week. MYC amplification led to high expression of MYC and rapid disease progression, indicating its clinical significance in the pathogenesis of MM/PCL. MYC amplification on dmin may be a very rare genetic event closely associated with the progression to PCL and coexistence of IGH/CCND1 fusions.

Case Report: Composite Angioimmunoblastic T-Cell Lymphoma and Epstein-Barr Virus-Positive B-Cell Lymphoproliferative Disorder as Other Iatrogenic Immunodeficiency-Associated Lymphoproliferative Disorders.

Immunosuppressants are widely used to treat patients with rheumatoid arthritis (RA), and their adverse effects have been known to cause other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPDs). We report a patient with RA who had been treated with methotrexate (MTX) and tacrolimus (TAC) and who developed whole body lymphadenopathy. We simultaneously confirmed angioimmunoblastic T-cell lymphoma (AITL) through a right cervical lymph node biopsy and Epstein-Barr virus-positive B-cell lymphoproliferative disorder (EBV-positive B-LPD) through a bone marrow examination. After cessation of immunosuppressant therapy, both LPDs completely disappeared. Patients with AITL are occasionally reported to develop B-cell lymphoma through reactivation of the EBV, which leads to clonal expansion in the microenvironment. Immunohistochemistry results revealed that both LPD components were positive for EBV-encoded RNA. Moreover, in this patient, the plasma EBV DNA level was found to be high; therefore, EBV infection was a probable etiology. Synchronous coexistence of AITL and B-LPD as an OIIA-LPD has rarely been reported. This case report is the first to discuss the disappearance of both LPDs on withdrawal of immunosuppressants only. AITL occasionally accompany B-LPD; however, this composite lymphoma comprised AITL and B-LPD, and OIIA-LPDs should not be overlooked.

[Systemic mastocytosis with refractory ascites successfully treated with interferon-α and a leukotriene receptor antagonist].

A 67-year-old male was referred to our hospital because of anemia, thrombocytopenia, and massive ascites. A diagnosis of systemic mastocytosis was made based on the observation of many mast cells in his bone marrow, elevated serum tryptase levels, and the presence of c-kit point mutation Asp816Val. Dasatinib and cladribine were ineffective, and a large volume of ascites was removed approximately every 3 days. Then, following an asthma attack, the patient was treated with pranlukast, a leukotriene receptor antagonist (LTRA). After LTRA treatment initiation, the frequency of ascites drainage decreased, and no puncture was necessary from the 10th day after the start of LTRA. Interferon α (IFN-α) was administered from the 15th day after the start of LTRA. Thereafter, his anemia and thrombocytopenia gradually improved, the ascites disappeared, the mast cells in his bone marrow were significantly reduced, and the Asp816Val mutation disappeared. Because persistent monocytosis was evident, he was suspected of chronic myelomonocytic leukemia but has not been diagnosed and is undergoing watchful waiting. This was considered to be a rare case of refractory ascites in which IFN-α was effective and LTRA might have been beneficial.

Laparoscopic hepatectomy for liver metastasis of lung large-cell neuroendocrine carcinoma: A case report.

INTRODUCTION: Lung large-cell neuroendocrine carcinoma (LCNEC) is an aggressive and a rare type of lung cancer, and the prognosis of LCNEC with distant metastasis is extremely poor, with a five-year survival rate of 0%. Here, we report a case of laparoscopic hepatectomy for liver metastasis of lung LCNEC. PRESENTATION OF CASE: A 63-year-old man received a routine physical examination, and abnormal chest radiographic findings were observed; chest computed tomography (CT) in our hospital revealed that the patient had left pneumothorax and a lesion measuring 18 mm in the inferior lingular segment of the lung. The patient underwent thoracoscopic lobectomy, and the final pathological diagnosis was lung LCNEC. Four years after surgery, abdominal CT revealed a mass measuring 27 mm in the liver. The patient underwent laparoscopic partial hepatectomy, and postoperative pathological examination showed liver metastasis of LCNEC. There was no sign of recurrence 6 months after hepatectomy. DISCUSSION: LCNEC with distant metastasis has a poor response to systemic chemotherapy, and the median survival time of patients with distant metastasis is estimated to be approximately 6 months, with a five-year survival rate of 0%. Although the common site of metastasis from LCNEC is the liver, there are no previous reports of hepatectomy for liver metastasis of LCNEC. CONCLUSION: We report a case of laparoscopic hepatectomy for liver metastasis of lung LCNEC. It is suggested that surgical resection for solitary distant metastasis of LCNEC may improve prognosis.

A rare case of metastatic solitary fibrous tumor of the pancreas manifesting as a cystic neoplasm: a case report.

BACKGROUND: Solitary fibrous tumor (SFT) is a rare mesenchymal tumor that typically arises from the pleura. Although it may appear in other organs, it rarely develops in the pancreas. We report herein a rare case of metastatic SFT of the pancreas originating from an intracranial tumor and subsequently identified as a cystic neoplasm of the pancreas. CASE PRESENTATION: A 58-year-old woman with a past medical history of brain tumor visited the hospital for further investigation of a cystic tumor in the pancreas tail. Abdominal imaging showed a heterogeneously enhancing mass that was initially suspected as a neuroendocrine neoplasm, solid pseudopapillary neoplasm, or mucinous cystic neoplasm of the pancreas. Distal pancreatectomy was performed without any intraoperative and postoperative complications. Pathological findings confirmed a diagnosis of malignant SFT of the pancreas with hyperproliferative potential. A histopathological review of her brain tumor revealed that the pancreatic tumor was derived from her brain lesion. The patient developed recurrent brain disease 4 years after the pancreatectomy, but no recurrence has been observed in the abdominal cavity. CONCLUSIONS: SFT should be considered in the differential diagnosis of untypical hypervascular pancreatic mass, particularly in patients with a history of an intrathoracic or intracranial mesenchymal tumor. Immunohistochemical analysis is crucial in detecting this tumor entity. Hyperproliferative status indicates a malignant disease and requires careful postoperative observation.

Double-hit pancreatic B-lymphoblastic lymphoma with a variant translocation t(2;18)(p11;q21).

Double-hit lymphoma is typically categorized as "high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements", but in infrequent cases in which terminal deoxynucleotidyl transferase (TdT) expression is positive, it is categorized as B-lymphoblastic lymphoma (B-LBL). BCL2 rearrangements are usually caused by t(14;18)(q32;q21); variant translocations are very rare. Here, we describe an unusual case of double-hit pancreatic B-LBL with a variant translocation t(2;18)(p11;q21). A 69-year-old man was admitted because of an abdominal mass. Computed tomography scans demonstrated a diffusely enlarged pancreas and massive ascites. Cell block preparations of ascites cells revealed marked proliferation of blastic lymphoid cells positive for CD19, CD10, CD79a, PAX5, and TdT, indicating a diagnosis of B-LBL. G-banding and spectral karyotyping showed 45,XY,+X,t(2;18)(p11;q21),-4,der(5)t(1;5)(q12;p15),der(6)t(6;21)(q21;q?),t(8;14)(q24;q32),-15. Fluorescence in situ hybridization detected split BCL2 and IGH/MYC fusion signals. Almost all ascites cells were diffusely and strongly positive for MYC and BCL2. The patient died of progressive disease 20 days after admission. To our knowledge, this is the first reported case of MYC and BCL2 double-hit B-LBL with t(2;18)(p11;q21). High coexpression of MYC by t(8;14) and BCL2 by t(2;18) may be implicated in the development of B-LBL. Furthermore, double-hit B-LBL may be associated with a less favorable outcome compared with typical B-LBL.

MYC Amplification in the Form of Ring Chromosomes 8 in Acute Myeloid Leukemia with t(11;16)(q13;p11.2).

Oncogene amplification is uncommon in acute myeloid leukemia (AML). Cytogenetically, it is primarily found as double minute chromosomes (dmin) or homogeneously staining regions (hsr). A 62-year-old woman was admitted to our hospital because of anemia and thrombocytopenia. Her bone marrow was hypercellular with 78.6% myeloperoxidase- positive blasts. Some had micronuclei. The patient was diagnosed with AML M2 and remains in complete remission (CR) after induction therapy. G-banding at diagnosis showed 51,XX,t(11;16)(q13;p11.2),+r1,+mar1×4. Spectral karyotyping confirmed t(11;16) and revealed that the ring and the marker chromosomes were derived from multiple copies of ring chromosome 8. Fluorescence in situ hybridization (FISH) with a MYC probe at 8q24 detected amplified MYC signals on 1 large and 4 small ring chromosomes 8. One MYC signal was deleted from one of the 2 chromosomes 8. FISH with a FUS probe at 16p11.2 showed monoallelic deletion of FUS. Immunohistochemistry demonstrated MYC protein overexpression at diagnosis and almost negative expression in CR. These results indicate that MYC amplification could occur in ring chromosomes without dmin. A cryptic MYC deletion suggests that an episome model could be applicable to MYC amplification in ring chromosomes as observed for dmin and hsr. Furthermore, considering 2 further reported cases, t(11;16)(q13;p11) may be a very rare but recurrent translocation in AML.

Paget's disease of the male breast: a case report.

The patient was a 91-year-old man with change in nipple appearance, itching and redness, and a palpable breast mass. At presentation, mammary Paget's disease (PD) was clinically suspected. Skin biopsy was performed and showed epidermis invaded by Paget cells, characterized by hyperchromatic nuclei and abundant pale-staining cytoplasm. Computed tomography and mammary ultrasonography confirmed the absence of an underlying invasive carcinoma, and the patient underwent right mastectomy and sentinel lymph node biopsy (SLNB). Both sentinel lymph nodes were found to be negative perioperatively, and further axillary dissection was not performed. Pathological results revealed no malignancy under the nipple, yet the Paget cells were more widely spread than expected. The patient was followed up without the need of postoperative chemotherapy. Male mammary PD is an extremely rare breast cancer, and there is no standard preoperative assessment or operative procedure. Mammography is many times unable to detect possible underlying breast carcinoma in female patients with mammary PD, and previous studies have reported that the detection rate was less than 50 %. However, some researchers reported that magnetic resonance imaging (MRI) might be more detectable to confirm the extent of the cancer. The extent of the skin change around the nipple is often different from the actual perimeter of Paget cells. In extra-mammary PD, mapping biopsy is known to be useful to determine areas free of cancer. The benefits of SLNB have also been demonstrated for the management of less invasive breast cancers, and previous reports have shown that the use of SLNB is reasonable for treatment of mammary PD without underlying invasive cancer. MRI, mapping biopsy, and SLNB are all less invasive procedures and thus may be suitable for treatment of male mammary PD.

Recurrence of lung adenocarcinoma after an interval of 15 years revealed by demonstration of the same type of EML4-ALK fusion gene.

We carried out an experiment on a 58-year-old man with multiple left lung tumors and swelling of multiple lymph nodes. For clinical staging and therapeutic purposes, bronchoalveolar lavage (BAL) cytology and lung biopsy were performed. The biopsy specimen revealed the left lower lung mass to be immunohistochemically ALK (anaplastic lymphoma kinase)-positive adenocarcinoma. Using the BAL specimen from the left lower lung, EML4 (echinoderm microtubule-associated protein-like 4)-ALK variant 1 fusion gene was detected by reverse transcription-polymerase chain reaction (RT-PCR). His past history showed that he had undergone an operation for lung adenocarcinoma of the right lower lobe 15 years before, and the pathological specimen at that time revealed that the lung adenocarcinoma with pleural invasion and single metastasis of mediastinal lymph node showed a mucinous cribriform pattern and/or signet-ring cell pattern. The typical histology led us to examine the ALK rearrangement in the primary lung cancer and mediastinal metastatic tumor. Immunohistochemistry (IHC) for ALK was positive, and ALK break apart fluorescence in situ hybridization (FISH) showed a positive result. Moreover, RT-PCR using formalin-fixed, paraffin-embedded tissue from the right lung cancer also demonstrated EML4-ALK variant 1 fusion gene. Although there is a possibility that the left lung cancer is de novo one with multiple metastases, detection of the same fusion gene of the very rare EML4-ALK variant 1 in both tumors suggests that the left cancer is a recurrence of the right lung cancer after an interval of 15 years.

A rare case of clear cell sarcoma with 4 types of EWSR1-ATF1 fusions detected not in primary site but in metastatic site.

Clear cell sarcoma is a unique tumor which has EWSR1-ATF1 or EWSR1-CREB1 fusion. Several patterns of EWSR1-ATF1 fusion are observed in clear cell sarcoma. Since type 5-7 fusions were reported recently, they are classified as type 1-7. We examined EWSR1-ATF1 and EWSR1-CREB1 fusions in a single case of clear cell sarcoma with lung metastasis in a 36-year-old Japanese man. As a result, we found only type 1 EWSR1-ATF1 fusion in the primary site, but 4 types of EWS-ATF1 fusion (type 1, 2, 5, 6) were detected in the metastatic site. These 4 types of fusion were completely identical to the recent report, but the case had the same fusion patterns in both primary and metastatic sites. In our case, increased splicing activity in the EWSR1-ATF1 fusion might be acquired at the metastatic site. There is another possibility that metastasis might develop through the increased splicing activity in the fusion.

Immunohistochemical profiling of ALK fusion gene-positive adenocarcinomas of the lung.

Our aim was to determine whether or not non-small-cell lung cancer is squamous cell carcinoma (SQCC); even in small samples, it is essential in view of the side effects attendant on new therapeutics. Lung adenocarcinoma (ADC) with the EML4-ALK fusion gene has been described as demonstrating mucinous cribriform/acinar growth and signet-ring cells, sometimes partially simulating SQCC. We investigated the relation among morphology, anaplastic lymphoma kinase (ALK) rearrangement, and immunophenotype in 321 ADCs by tissue microarray using SQCC markers cytokeratin (CK)5/6, CK14, desmocollin-3, desmoglein-3, p40, p63 versus ADC markers thyroid transcription factor (TTF)-1 and napsin A. Unlike 312 ALK-negative ADCs, 9 ALK-positive cases were negative for 4 SQCC markers. Only 1 ALK-positive ADC showing assertive morphology was positive for CK5/6 and p63 as well as for TTF-1 and napsin A. Coexpression of TTF-1/p40 was not observed, unlike that of TTF-1/p63 reported previously. There was no statistically significant difference between ALK-negative and ALK-positive ADC by immunohistochemical profiling.

Significance of microscopic invasion into hilar peribronchovascular soft tissue in resection specimens of primary non-small cell lung cancer.

INTRODUCTION: The significance and handling of microscopic invasion of non-small cell lung cancer (NSCLC) into hilar peribronchovascular soft tissue (SHEATH+) have not been defined in the TNM classification by AJCC/UICC; nevertheless, SHEATH+ may be equivalent to spread into the mediastinum. Also, assessment of the margin of peribronchial resection is challenging because of the technical difficulty of inking, and intraoperative and postoperative artifacts. METHODS: Records of 592 consecutive Asian patients with primary NSCLC (excluding adenocarcinoma in situ) who had, without any preoperative therapy, undergone lobectomy, sleeve lobectomy and pneumonectomy were examined. SHEATH+, simply defined as invasion of hilar peribronchovascular soft tissue, without categorizing any invasive patterns, and its significance were statistically analyzed. RESULTS: Forty-four SHEATH+ cases demonstrated significantly advanced TNM stages, and were statistically associated with central occurrence, pN1-3, and vascular invasion, as assessed by logistic regression analysis. No statistically significant differences were observed between TNM stage-adjusted frequency of recurrence and recurrence-free intervals. Kaplan-Meier's estimates of the rate of overall and recurrence-free survival after surgery showed no statistically significant differences between SHEATH+ and SHEATH-. Cox's multivariate analysis suggested SHEATH was not a statistically independent prognostic factor under the TNM classification by AJCC/UICC (7th edition). CONCLUSIONS: SHEATH+ in NSCLC was simply associated with central occurrence and advanced TNM stages. To the best of our knowledge, this is the first report on the significance of SHEATH+ in NSCLC.